PDC Expansion of Natural TREG Cells Limits Severe-Pneumovirus-Induced Bronchiolitis and Attenuates the Onset of Virus-Provoked Asthma

Circulating plasmacytoid dendritic cells (pDC) are inversely associated with infant wheeze, bronchiolitis and childhood asthma. Here we addressed whether inducible depletion of pDC in early-life alone increases the severity of Pneumovirus infection and predisposes toward virus-provoked asthma. Temporary depletion of pDC (using pDC-DTR neonatal mice) attenuated interferon alpha and lambda production in the lung, increased viral load in the airway epithelium and promoted severe bronchiolitis (neutrophilia, sloughing and weight loss) during low dose pneumonia virus of mice infection (10 plaque forming units, intranasal route) in early-life. Heightened inflammation was associated with significantly lower numbers of neuropilin-1+ natural regulatory T cells (nTreg), but not peripherally-induced Treg, and diminished IL-10 and TGF-β production in the lung. Relative to other antigen presenting cells, the neuropilin-1 ligand semaphorin-4a was highly expressed on pDC and ligation of neuropilin-1, but not the interferon alpha receptor, was necessary for pDC mediated expansion of nTreg. Viral challenge of pDC-DTR but not WT mice in later-life (6 weeks later) induced the hallmark features of asthma, including airway hyperreactivity, eosinophilia and type-2 inflammation. Adoptive transfer of naïve nTreg during primary infection of pDC-depleted mice prevented the development of both severe bronchiolitis and post-viral asthma. These data are the first to demonstrate that pDC-mediated support of nTreg is necessary to limit severe virus-induced bronchiolitis, and is sufficient to halt the onset of childhood asthma. We propose that boosting the tolerogenic function of pDC in early-life represents a novel preventative strategy for the treatment of both bronchiolitis and asthma.